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Frontiers in Pharmacology 2024Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish...
BACKGROUND
Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish the safety profile of lorlatinib based on the Food and Drug Administration Adverse Event Reporting System (FAERS).
METHODS
Reports from the FAERS between 2019 and 2023 were collected to conduct the disproportionality analysis. Reporting odds ratio (ROR) was employed to detect the potential adverse events (AEs) related to lorlatinib. The clinical characteristics, age and gender differences, time to onset of AEs were also investigated.
RESULTS
A total of 2,941 AE reports were found to be associated with lorlatinib among the 8,818,870 AE reports obtained from the FAERS database. 167 lorlatinib-related AE signals were identified. The frequently reported AEs including hypercholesterolemia, oedema, and cognitive disorder were in line with those observed in clinical trials and drug instruction. However, AEs such as interstitial lung disease and AV block indicated in the drug label require further evaluation. More attention should be paid to the new potential unexpected AEs including pulmonary arterial hypertension and radiation necrosis. Furthermore, we examined the specific high-risk AEs of different ages and genders. In addition, majority of AEs occurred within the first 2 months after lorlatinib initiation with a median onset time of 51 days.
CONCLUSION
Our study provides valuable insight into the post-marketing safety profile of lorlatinib, which can potentially benefit the rational and safe administration of lorlatinib in the clinic. Further prospective studies are needed to validate the associations between lorlatinib and the identified AEs.
PubMed: 38903993
DOI: 10.3389/fphar.2024.1385036 -
Journal of Neuro-oncology Jun 2024GammaTile® (GT) is a brachytherapy platform that received Federal Drug Administration (FDA) approval as brain tumor therapy in late 2018. Here, we reviewed our...
PURPOSE
GammaTile® (GT) is a brachytherapy platform that received Federal Drug Administration (FDA) approval as brain tumor therapy in late 2018. Here, we reviewed our institutional experience with GT as treatment for recurrent glioblastomas and characterized dosimetric parameter and associated clinical outcome.
METHODS AND MATERIALS
A total of 20 consecutive patients with 21 (n = 21) diagnosis of recurrent glioblastoma underwent resection followed by intraoperative GT implant between 01/2019 and 12/2020. Data on gross tumor volume (GTV), number of GT units implanted, dose coverage for the high-risk clinical target volume (HR-CTV), measured by D or dose received by 90% of the HR-CTV, dose to organs at risk, and six months local control were collected.
RESULTS
The median D to HR-CTV was 56.0 Gy (31.7-98.7 Gy). The brainstem, optic chiasm, ipsilateral optic nerve, and ipsilateral hippocampus median D were 11.2, 5.4, 6.4, and 10.0 Gy, respectively. None of the patients in this study cohort suffered from radiation necrosis or adverse events attributable to the GT. Correlation was found between pre-op GTV, the volume of the resection cavity, and the number of GT units implanted. Of the resection cavities, 7/21 (33%) of the cavity experienced shrinkage, 3/21 (14%) remained stable, and 11/21 (52%) of the cavities expanded on the 3-months post-resection/GT implant MRIs. D to HR-CTV was found to be associated with local recurrence at 6-month post GT implant, suggesting a dose response relationship (p = 0.026). The median local recurrence-free survival was 366.5 days (64-1,098 days), and a trend towards improved local recurrence-free survival was seen in patients with D to HR-CTV ≥ 56 Gy (p = 0.048).
CONCLUSIONS
Our pilot, institutional experience provides clinical outcome, dosimetric considerations, and offer technical guidance in the clinical implementation of GT brachytherapy.
PubMed: 38902561
DOI: 10.1007/s11060-024-04631-4 -
Free Radical Biology & Medicine Jun 2024Repeated sevoflurane exposure in neonatal mice triggers neuroinflammation with detrimental effects on cognitive function. Yet, the mechanism of the sevoflurane-induced...
Repeated sevoflurane exposure in neonatal mice triggers neuroinflammation with detrimental effects on cognitive function. Yet, the mechanism of the sevoflurane-induced cytokine response is largely unknown. In this study, we reveal that 3-MA, an autophagy inhibitor, attenuated the sevoflurane-induced neuroinflammation and cognitive dysfunction, including the decreased freezing time and fewer platform crossings, in the neonate mice. 3-Methyladenine (3-MA) suppressed sevoflurane-induced expression of interleukin-6 and tumor necrosis factor-alpha in vitro. Moreover, sevoflurane activates IRF3, facilitating cytokine transcription in an AKT3-dependent manner. Mechanistically, sevoflurane-induced autophagic degradation of dehydrocholesterol-reductase-7 (DHCR7) resulted in accumulations of its substrate 7-dehydrocholesterol (7-DHC), mimicking the effect of sevoflurane on AKT3 activation and IRF3-driven cytokine expression. 3-MA significantly reversed sevoflurane-induced DHCR7 degradation, AKT phosphorylation, IRF3 activation, and the accumulation of 7-DHC in the hippocampal CA1 region. These findings pave the way for additional investigations aimed at developing novel strategies to mitigate postoperative cognitive impairment in pediatric patients.
PubMed: 38901498
DOI: 10.1016/j.freeradbiomed.2024.06.012 -
ESMO Open Jun 2024
Concurrent antibody-drug conjugates and radiotherapy: a new perspective on radiation necrosis in HER2-positive breast cancer brain metastases from the DESTINY-Breast03 and HER2CLIMB trials.
PubMed: 38897137
DOI: 10.1016/j.esmoop.2024.103620 -
Journal of Clinical Medicine Jun 2024Non-seminomatous germ cell tumors (NSGCTs) represent a rare yet the most prevalent malignancy among young men. Bone metastases (BMs) are exceedingly uncommon in this...
Non-seminomatous germ cell tumors (NSGCTs) represent a rare yet the most prevalent malignancy among young men. Bone metastases (BMs) are exceedingly uncommon in this neoplasm, and available data regarding the initial disease presentation, survival outcomes, and prognostic significance of BMs are limited. We conducted a retrospective analysis of 40 NSGCT patients with BMs treated between 2001 and 2021 in our tertiary care center. The cohort was stratified into synchronous (n = 29) and metachronous (n = 11) groups based on the presence of BM at diagnosis or only at relapse, respectively. We assessed overall survival (OS), progression-free survival (PFS), disease presentation, and treatments. After a median follow-up of 93 months, the 5-year PFS and OS rates were 37.6% and 53.9% in the synchronous group and 18.2% and 36.4% in the metachronous group, respectively. At the initial diagnosis, most patients were classified into the IGCCCG poor prognostic group (n = 34, 85%). BMs were mostly asymptomatic (n = 23, 57.5%), involved the spine (n = 37, 92.5%), and could become visible only after disease response (n = 4, 10%). A pathological examination of resected bone lesions after first-line treatment revealed necrosis (n = 5, 71.4%), teratoma, or seminoma (both n = 1, 14.3%). At first relapse, eight patients in the synchronous group did not experience bone recurrence, while eight patients experienced recurrence at the initial affected bone site. In NSGCT patients, BMs often present asymptomatically and may initially be unnoticed. However, these patients may have a poorer prognosis compared to those in the IGCCCG poor prognostic group. Further studies including control groups are needed to assess the independent prognostic significance of BMs.
PubMed: 38892991
DOI: 10.3390/jcm13113280 -
International Journal of Molecular... May 2024Astronauts on exploratory missions will be exposed to galactic cosmic rays (GCR), which can induce neuroinflammation and oxidative stress (OS) and may increase the risk...
Astronauts on exploratory missions will be exposed to galactic cosmic rays (GCR), which can induce neuroinflammation and oxidative stress (OS) and may increase the risk of neurodegenerative disease. As key regulators of inflammation and OS in the CNS, microglial cells may be involved in GCR-induced deficits, and therefore could be a target for neuroprotection. This study assessed the effects of exposure to helium (He) and iron (Fe) particles on inflammation and OS in microglia in vitro, to establish a model for testing countermeasure efficacy. Rat microglia were exposed to a single dose of 20 cGy (300 MeV/n) He or 2 Gy Fe (600 MeV/n), while the control cells were not exposed (0 cGy). Immediately following irradiation, fresh media was applied to the cells, and biomarkers of inflammation (cyclooxygenase-2 [COX-2], nitric oxide synthase [iNOS], phosphorylated IκB-α [pIκB-α], tumor necrosis factor-α [TNFα], and nitrite [NO]) and OS (NADPH oxidase [NOX2]) were assessed 24 h later using standard immunochemical techniques. Results showed that radiation did not increase levels of NO or protein levels of COX-2, iNOS, pIκB-α, TNFα, or NOX2 compared to non-irradiated control conditions in microglial cells ( > 0.05). Therefore, microglia in isolation may not be the primary cause of neuroinflammation and OS following exposures to helium or iron GCR particles.
Topics: Animals; Microglia; Cosmic Radiation; Oxidative Stress; Rats; Inflammation; Biomarkers; Nitric Oxide Synthase Type II; Iron; Cyclooxygenase 2; Helium; Tumor Necrosis Factor-alpha; NADPH Oxidase 2
PubMed: 38892109
DOI: 10.3390/ijms25115923 -
International Journal of Molecular... May 2024Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have...
Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2β did not differ between groups ( > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.
Topics: Animals; Liraglutide; Doxorubicin; Cardiotoxicity; Male; Rats; Rats, Wistar; Oxidative Stress; Myocardium; NF-kappa B; Tumor Necrosis Factor-alpha; Heart
PubMed: 38892020
DOI: 10.3390/ijms25115833 -
International Journal of Molecular... May 2024Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA)...
Astatine (At) is a cyclotron-produced alpha emitter with a physical half-life of 7.2 h. In our previous study, the At-labeled prostate-specific membrane antigen (PSMA) compound ([At]PSMA-5) exhibited excellent tumor growth suppression in a xenograft model. We conducted preclinical biodistribution and toxicity studies for the first-in-human clinical trial. [At]PSMA-5 was administered to both normal male ICR mice ( = 85) and cynomolgus monkeys ( = 2). The mice were divided into four groups for the toxicity study: 5 MBq/kg, 12 MBq/kg, 35 MBq/kg, and vehicle control, with follow-ups at 1 day ( = 10 per group) and 14 days ( = 5 per group). Monkeys were observed 24 h post-administration of [At]PSMA-5 (9 MBq/kg). Blood tests and histopathological examinations were performed at the end of the observation period. Blood tests in mice indicated no significant myelosuppression or renal dysfunction. However, the monkeys displayed mild leukopenia 24 h post-administration. Despite the high accumulation in the kidneys and thyroid, histological analysis revealed no abnormalities. On day 1, dose-dependent single-cell necrosis/apoptosis was observed in the salivary glands of mice and intestinal tracts of both mice and monkeys. Additionally, tingible body macrophages in the spleen and lymph nodes indicated phagocytosis of apoptotic B lymphocytes. Cortical lymphopenia (2/10) in the thymus and a decrease in the bone marrow cells (9/10) were observed in the 35 MBq/kg group in mice. These changes were transient, with no irreversible toxicity observed in mice 14 days post-administration. This study identified no severe toxicities associated with [At]PSMA-5, highlighting its potential as a next-generation targeted alpha therapy for prostate cancer. The sustainable production of At using a cyclotron supports its applicability for clinical use.
Topics: Animals; Male; Prostatic Neoplasms; Mice; Tissue Distribution; Mice, Inbred ICR; Astatine; Alpha Particles; Humans; Macaca fascicularis; Glutamate Carboxypeptidase II; Radiopharmaceuticals
PubMed: 38891856
DOI: 10.3390/ijms25115667 -
International Journal of Molecular... May 2024(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects...
(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.
Topics: Humans; Phthalazines; Indazoles; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Cell Line, Tumor; Radiation-Sensitizing Agents; Squamous Cell Carcinoma of Head and Neck; Apoptosis; Head and Neck Neoplasms; DNA-Activated Protein Kinase
PubMed: 38891817
DOI: 10.3390/ijms25115629 -
BMC Musculoskeletal Disorders Jun 2024At present, the core decompression (CD) has become the main surgical procedure for the treatment of osteonecrosis of the femoral head (ONFH); however, the CD surgery... (Meta-Analysis)
Meta-Analysis Comparative Study
Comparison of clinical efficacy of robot-assisted and freehand core decompression in the treatment of osteonecrosis of the femoral head: a systematic review and meta-analysis.
OBJECTIVE
At present, the core decompression (CD) has become the main surgical procedure for the treatment of osteonecrosis of the femoral head (ONFH); however, the CD surgery requires high operator experience and repeated fluoroscopy increases the radiation damage to patients, and medical staff. This article compares the clinical efficacy of robot-assisted and freehand CD for ONFH by meta-analysis.
METHODS
Computer searches of PubMed, Web of Science, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang, and Chinese BioMedical Literature Database were conducted from the time of database inception to November 15, 2023. The literature on the clinical efficacy of robot-assisted and freehand CD in the treatment of ONFH was collected. Two researchers independently screened the literature according to the inclusion and exclusion criteria, extracted data, and strictly evaluated the quality of the included literature. Outcome measures encompassed operative duration, intraoperative blood loss volume, frequency of intraoperative fluoroscopies, visual analog scale (VAS) score, Harris hip score (HHS), complications, and radiographic progression. Data synthesis was carried out using Review Manager 5.4.1 software. The quality of evidence was evaluated according to Grades of Recommendation Assessment Development and Evaluation (GRADE) standards.
RESULTS
Seven retrospective cohort studies involving 355 patients were included in the study. The results of meta-analysis showed that in the robot-assisted group, the operative duration (MD = -17.60, 95% CI: -23.41 to -11.78, P < 0.001), intraoperative blood loss volume (MD = -19.98, 95% CI: -28.84 to -11.11, P < 0.001), frequency of intraoperative fluoroscopies (MD = -6.60, 95% CI: -9.01 to -4.20, P < 0.001), and ΔVAS score (MD = -0.45, 95% CI: -0.67 to -0.22, P < 0.001) were significantly better than those in the freehand group. The GRADE evidence evaluation showed ΔVAS score as low quality and other indicators as very low quality. There was no significant difference in the terms of ΔHHS (MD = 0.51, 95% CI: -1.34 to 2.35, P = 0.59), complications (RR = 0.30, 95% CI: 0.03 to 2.74, P = 0.29), and radiographic progression (RR = 0.50, 95% CI: 0.25 to 1.02, P = 0.06) between the two groups.
CONCLUSION
There is limited evidence showing the benefit of robot-assisted therapy for treatment of ONFH patients, and much of it is of low quality. Therefore, caution should be exercised in interpreting these results. It is recommended that more high-quality studies be conducted to validate these findings in future studies.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/ #recordDetails, CRD42023420593.
Topics: Humans; Femur Head Necrosis; Decompression, Surgical; Treatment Outcome; Robotic Surgical Procedures; Operative Time
PubMed: 38890631
DOI: 10.1186/s12891-024-07592-x